Note: Descriptions are shown in the official language in which they were submitted.
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SPECIFIC~TION
Medicinal adhesive sheets for heart diseases ;
and a process for the preparation thereof
Technical Field
The present invention relates to medicinal adhesive
sheets usable for the medical treatment and prevention
of heart diseases. More particularly, the present
invention relates to medicinal adhesive sheets containing
nitroglycerin for heart diseases as the principal ingre-
dient.
Background Art
Nitroglycerin has long been used for the internal
treatment of ischemic heart diseases. Nitroglycerin has
been administered in the form of various preparations
such as intravenous injection, sublingual tablets arid
ointments. The duration of the effects of intravenous
injections, sublingual tablets and ointments are several
minutes, 20-30 minutes and 3-5 hours, respectively.
Generally, sublingual tablets are used for the
treatment of angina pectoris. However, their effects
are short lived, and the sublingual tablets are therefore
unsuitable for preventing an attack.
A nitroglycerin-containing ointment is used when the
effects of nitroglycerin are to be maintained for a long
period of time (for example, in preventing angina pectoris)O
,, .
. ~
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When ointment is used, a suitable amount of the ointment
is applied to the skin of the patient's chest and is then
covered with a plastic film or the like and to prevent the
volatilization of the nitroglycerin and staining of his
clothes. The suitable amount of ointment is an amount
slightly smaller than that which causes a headache. The
ointment is applied in various amounts to the respective -
patients to determine the proper amount experimentally.
At present, the amount of ointment is estimated from the
length of the bead extruded from the tube, so determina-
tion of the precise quantity of the ointment is difficult.
Further, the use of ointment is troublesome as described
above.
(Prior Art)
Recently, medicinal adhesive sheets containing
nitroglycerin have been proposed (see the specification
of Japanese Patent Laid-Open No. 2604/1980). However,
the nitroglycerin retention and release of the sheets
are unsatisfactory, since the adhesive contained therein
has not been improved (an adhesive plaster base is used)O
Copolymers of alkyl acrylates or alkyl methacrylates
in which the alkyl group contains 4-12 carbon atoms have
generally been used as adhesives only slightly irritating
the skin. However, these conventional adhesives have a
high ability to adsorb nitroglycerin and, therefore, a low
1175746
nitroglycerin-releasing property. Thus, they are unsuitable
for use as a carrier for nitroglycerin which is to be
released as an active ingredient.
(Object of the Invention)
After investigations on adhesives having only a
slight irritating effect on the skin and an excellent
nitroglycerin-releasing property made under the above
circumstances, the inventors have accomplished the present
invention and the object has been attained.
Disclosure of the Invention
(Construction of the Invention)
The object of the present invention has been attained
by using a new copolymer developed by the inventors as an
adhesive of an adhesive composition for medicinal adhesive
sheets for heart diseases. The new copolymer is obtained
by copoly~erizing:
(a) about 60~98 parts by weight of dodecyl methacrylate,
(b) about 2-40 parts by weight of a functional monomer,
and
(c) about 0-40 parts by weight of at least one short
chain unsaturated ~onomer selected from the group
consisting of vinyl acetate, alkyl acrylates in
which the alkyl group contains 1-8 carbon atoms
and alkyl methacrylates in which the alkyl group
contains 1-8 carbon atoms.
_ 4 _ ~75~4~
In the present invention, the medicinal adhesive sheet
for heart diseases is prepared by applying an adhesive
composition containing the above copolymer and a suitable
amount of nitroglycerin as the essential ingredient to a
suitable base.
Thus, according to the invention there is provided a
process for preparing a medicinal adhesive sheet, which
comprises providing a nitroglycerin-containing adhesive
layer on a base, wherein said layer comprises a copolymer
obtained by copolymerizing (a~ about 60-98 parts by weight
of dodecyl methacrylate, (b) about 40-2 parts by weight of
a functional monomer, and (c) about 0-40 parts by weight
of at least one short chain unsaturated monomer selected
from the group consisting of vinyl acetate, alkyl acrylates
in which the alkyl group contains 1 to 8 carbon atoms and
alkyl methacrylates in which the alkyl group contains 1 to
8 carbon atoms.
The description will be made on the constituents of
the present invention.
(Copolymer)
(a) The suitable amount of dodecyl methacrylate constitu-
ting the copolymer according to the present invention is
about 60-98 parts by weight as described above, and, more
preferably, about 70-95 parts by weight.
(b) Suitable functional monomers according to the present
invention include acrylic acid, methacrylic acid,
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acrylamide, methacrylamide, hydroxyethyl acrylate and
hydroxyethyl methacrylate. Approximately 2-40 parts by
weight, preferably about 2-10 parts by weight of the
functional monomer is used. If the amount of the
functional monomer is more than 40 parts by weight, the
resulting copolymer has reduced adhesive power and a
reduced nitroglycerin-releasing property. If the amount
of the functional monomer is less than 2 parts by weight,
the cohesive strength of the copolymer is insufficient and
the copolymer becomes soft and sticky. Accordingly, in
the latter case, the adhesive composition remains on the
skin after the adhesive sheet
~ ,~,
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has been peeled off.
tc) At least one short chain unsaturated monomer selected
from the group consisting of vinyl acetate, alkyl acrylates
in which the alkyl group contains 1-8 carbon atoms and
alkyl methacrylates in which the alkyl group contains 1-8
carbon atoms can be used in an amount in the range of
about 0-40 parts by weight, preferably up to about 30
parts by weight~ The amount of these short chain unsaturated
monomers should be determined in due consideration of the
variety and amount of the above functional monomer (b),
since they are used for controlling the cohesive strength
of the copolymer depending on the variety and amount of
monomer (b~.
The copolymer used as the adhesive according to the
present invention can be prepared by dissolving the
monomers in a suitable solvent and heating the resulting
solution to a suitable temperature under polymerization
conditions. If a proper polymerization initiator is
incorporated in the mixture in the polymerization vessel,
the polymerization temperature can be lowered and the
polymerization tlme required for obtaining a copolymer of
a desired molecular weight can be reduced.
Ethyl acetate, n-hexane and toluene may be mentioned
as organic solvents used for the preparation of the
copolymer to be used as the adhesive.
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A suitable reaction temperature for the preparation
of the above copolymer is about 70C.
A peroxide, particularly dodecyl peroxide, is a
suitable polymerization initiator for preparation of the
above copolymer. If a large amount of peroxide is used,
it becomes difficult to control-the polymerization
procedure, though the polymerization reaction velocity is
increased. On the other hand, if a small amount of
peroxide is used, the polymerization reaction velocity is
lowered and the molecular weight of the copolymer is apt
to become too high. In case dodecyl peroxide is used, an
amount of 12 parts by weight per l,000 parts by weight of
monomer mixture is suitable.
Peroxide i5 suitably used in the form of a solution
lS with an organic solvent such as n-hexane. The peroxide
solution is added to the mixture in the copolymerization
reaction vessel when the temperature of the contents of
the reaction vessel reaches the desired polymerization
temperature (70C). For safety, it is desirable to add
the peroxide solution in small portions over, say, a
period of one hour.
Under the above polymerization conditions, the poly-
merization time is preferably about 7-8 hours after the
addition of the peroxide.
After completion of the polymerization reaction, a
~757~L6
suitable organic solvent such as n-hexane is added to the
reaction mixture in the vessel to dilute the copolymer
solution, which is then removed from the vessel.
The copolymer content of the thus obtained copolymer
solution is controlled to a concentration of 40 % to obtain
an adhesive solution. The adhesive solution has a viscosity
of about 160-550 poises at 30C, as measured by a rotational
viscometer. The viscosity of the thin film obtained by
removing the solvent from the copolymer solution is about
0 9 X 10 6 poises to 7 X 10 7 poises as measured by the shearing
creep method.
(Preparation of the adhesive composition)
In preparing the medicinal adhesive sheets of the
present invention, nitroglycerin is incorporated in the
above copolymer solution in an amount to yield a content
of 1-20 mg, preferably 5-15 mg, per 100 cm2 of sheet.
Nitroglycerin is incorporated in the above copolymer
solution by mixing the copolymer solution diluted with the
organic solvent with a solution of nitroglycerin in an
organic solvent in an ordinary manner.
The organic solvent in which the nitroglycerin is
dissolved should not coagulate the copolymer when it is
mixed with the copolymer solution. In regard to this
point, ethyl acetate is suitable as the organic solvent
for nitroglycerin. The nitroglycerin concentration in
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the solution with the organic solvent should be low enough
to avoid danger of explosion. A suitable concentration
thereof is in the range of about 3 to 7 wt. ~.
A suitable softener may be incorporated in the adhe-
sive composi-tion of the medicinal adhesive sheets of the
present invention so as to improve the adhesion of the
composition and to control the retention and release of
nitroglycerin. Suitable softeners are long chain fatty
acid esters such as isopropyl myristate and isopropyl
lanolin fatty acid esters; lanolin derivatives such as
refined lanolin, hydrogenated lanolin, lanolin alcohols
and lanolin acetate; fatty acid monoglycerides such as
glycerin monostearate; oils and fats such as hydrogenated
castor oil; low softening point resins such as methyl
ester of hydrogenated rosin; and vaseline. These softeners
are used in an amount of about 5 to 40 parts by weight per
lO0 parts by weight of adhesive.
(Base)
Materials used as the base of the medicinal adhesive
sheets of the present invention are those generally used
as the base of adhesive tapes but they should neither be
permeable to nitroglycerin nor inhibit the release of
nitroglycerin. Arnong them, polyolefins such as polyethylene
and polypropylene are most suitable from the viewpoint of
stability on standing.
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g
(Method of applying the adheslve composition to the base)
The medicinal adhesive sheets of the present inven-
tion comprise the above adhesive composition adhered to
a base. The adhesive composition may be applied to the
base by the coating method or the transfer method generally
employed for the preparation of adhesive tapes.
The medicinal adhesive sheets of the present inven-
tion may be prepared also by a new precise transfer method.
This new method will be illustrated below.
Step 1
A silicone resin is applied to a polyethylene layer
of a release paper comprising a laminate of paper and a
polyethylene layer. A solution of dodecyl methacrylate
copolymer of the present invention is applied to the
silicone-treated surface and then dried.
Step 2
One surface of a plastic film (i.e. the base) such
as flexible polyethylene film is corona-treated and the
other surface is mat-finished. The corona~treated surface
of the thus obtained base and the copolymer surface of the
composite (release paper carrying the copolymer) obtained
in above step 1 are attached together to obtain a sheet
in which the copolymer is interposed between the release
paper and the base.
Step 3
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Silicone resin is applied to the surface of a plastic
film having high dimensional stability, such as a poly-
ethylene terephthalate film, to form a separator. A
nitroglycerin-containing ointment is applied to the
silicone-treated surface. The nitroglycerin-containing
ointment comprises a softener such as refined lanolin in
which nitroglycerin is homogeneously dispersed.
S-tep 4
The release paper is removed from the copolymer sheet
having the release paper and the base obtained in above
step 2 to expose the copolymer. The copolymer surface and
the ointment surface on the separator obtained in above
step 3 are adhered together. The thus obtained composite
is heated to a temperature of 25-60C, preferably 40-50C
(at which nitroglycerin is neither volatilized nor decom-
posed), and the composite is kept at that temperature for
several days (for example, 6-8 days) to age it. By this
treatment, the nitroglycerin-containing ointment is
diffused in the copolymer to form a homogeneous nitro-
glycerin-containing adhesive composition on the base, and
the medicinal adhesive sheet having the separator of the
present invention is thus obtained.
According to the new transfer method above, the sheet
of the present invention can be prepared with constant,
stable precision.
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However, when the sheet does not need to be of high
precision, a simplified transfer method may be employed
in place of the above new transfer method. The simplified
transfer method consists of the following:
Step 1
One surface of a plastic film (i.e. the base) such
as polypropylene film is corona-treated and the other
surface thereof is mat-finished. The dodecyl methacrylate
copolymer of the present invention is applied to the
corona-treated surface of the base to obtain a copolymer
sheet carried on the base.
Step 2
The same treatment as in step 3 of the precise
transfer method is carried out.
Step 3
The copolymer surface of the copolymer sheet obtained
in step 1 and the ointment surface on the separator
obtained in above step 2 are adhered together. Thus
resulting composite is heated and aged in the same manner
as in the second half of step 4 of the above precise
transfer method to obtain the medicinal adhesive sheet
of the present invention.
(Shape of the medicinal adhesive sheet)
The medicinal adhesive sheet of the present invention
may be in the form of a roll like an adhesive tape or,
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more preferably, in the form of suitably sized sheets.
If it is in the form of sheets, it is easy for the
patients to control the dosage. If each sheet is sealed
in an aluminum bag, the volatilization of nitroglycerin
can be prevented until use.
When the sheets are prepared, a separator should be
adhered to the adhesive composition. As materials for
the separator, those which prevent migration of nitro-
glycerin on standing, such as polyesters, polyethylene,
polypropylene and aluminum-laminated polyolefins, may be
used. The surface of the separator in contact with the
adhesive composition is preferably treated with a silicone
resin to facilitate its release from the adhesive com-
position.
(Functions and effects of the present invention)
High molecular substances having dodecyl methacrylate
as the main monomer have hardly been used as a component
of an adhesive composition in the prior art. The medi-
cinal adhesive sheet of the present invention is charac-
terized by such a copolymer as the main component of theadhesive composition.
The medicinal adhesive sheet of the present invention
has a good balance between adhesiveness and cohesive
strength of the adhesive composition, and exhibits only
slight irritation to the skin.
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Known acrylic adhesives (for example polymers such
as poly-2-ethylhexyl acrylate) generally have an offensive
smell, but the dodecyl methacrylate copolymers contained
in the medicinal adhesive sheet of the present invention
have no unpleasant smell and, therefore, the sheet of
this invention is more comfortable to use.
As compared with a medicinal adhesive sheet containing
an adhesive composition containing an alkyl acrylate or
alkyl methacrylate in which the alkyl group contains 4-8
carbon atoms as the main component, the medicinal adhesive
sheet of the present invention has a superior nitroglycerin-
releasing property. Examples from tests are given below.
(Sample A)
An adhesive sheet was prepared from an ordinary
acrylic copolymer composition comprising 85 wt. ~ of
2-ethylhexyl acrylate as the main constituent and 10 wt.
% of vinyl acetate and 5 wt. % of acrylic acid as sub-
constituents (viscosity of a 40 wt. % solution in a mixture
of toluene and cyclohexane at 30C was 60 poises) and
containing 2 %, based on the solid content of the acrylic
copolymer, of nitroglycerin. The adhesive sheet had a
polyethylene base and an adhesive layer thickness of 40
microns. The nitroglycerin elution rate from the adhesive
sheet into a phosphate buffer physiological salt solution
(pH 6.0) was about 18 % at 37C after 60 minutes.
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Sections (5 X 7 cm2) (actual nitroglycerin content: 2.8
mg) of the sheet were applied to normal human subjects
but no reaction was recognized.
(Sample B)
The elution rate of an adhesive sheet prepared from
a solution of dodecyl methacrylate copolymer (comprising
86 wt. % of dodecyl methacrylate as main ingredient and
10 wt. % of vinyl acetate and 4 wt. % of acrylic acid as
sub-constituents) obtained according to "Preparation
Example 1 for adhesive copolymer solution" given below
and containing 2 %, based on the solid content of the
copolymer, of nitroglycerln was improved to about 46 %
under the same conditions as in the test of Sample A.
Sections (5 X 7 cm2) (actual nitroglycerin content: 3.0
mg) of the sheet were applied to normal human subjects.
Approximately two hours after application a slight
headache and elevation of heart rate were recognized.
About 40 minutes after removal of the test pieces the
subjective symptoms disappeared.
Brief Description of the Drawings
Fig. 1 is a line graph showing the test results of
the medicinal adhesive sheet of the present inventionD
Line 1 indicates heart rate, line 2 indicates systolic
blood pressure and line 3 indicates diastolic blood
pressure.
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Fig. 2 illustrates the respective steps in the
preparation method shown in Example 2. In Fig. 2, (a)
shows a release paper with copolymer applied, (b) shows
the copolymer affixed to a base, (c) shows the copolymer
from whlch the release papex has been peeled, (d) shows
a nitroglycerin-containing softener applied to a separator,
(e) shows (c) affixed to (d), and (f) shows the condition
after aging (e). In Fig. 2, 1 represents a release paper,
2 represents a copolymer, 3 represents a base, 4 represents
a separator, S represents a nitroglycerin-containing
ointment and 6 represents a nitroglycerin-containing
adhesive composition.
Best ~ode for Carrying Out the Invention
Before the description of embodiments of the medici-
nal adhesive sheets of the present invention, a descriptionof the methods of preparing copolymer adhesive solutions
used for the preparation of the adhesive compositions will
be given.
Preparation Example 1 of the adhesive copolymer solution:
860 g of dodecyl methacrylate, 100 g of vinyl
acetate, 40 g of acrylic acid, 560 g of n-hexane and 120 g
of toluene is charged in a 4 Q four-necked flask provided
with a nitrogen inlet, reflux condenser, stirrer and
thermometer. The whole is heated in a water bath and
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stirred while nitrogen is introduced therein. When the
inner temperature reaches 70C, a solution of 12 g of
dodecyl peroxide as initiator dissolved in 88 g of n-
hexane is slowly added over a period of one hour. The
reaction is continued for 7 hours. After completion of
the polymerization reaction, 720 g of n-hexane is added
to the mixture to dilute the same, thereby obtaining
2500 g of an adhesive solution having a concentration
of about 40 ~. The solution has a viscosity of 166
poises, determined with a rotational viscometer at 30C.
After the remova~ of the solvent, the resulting thin
film of the adhesive solution has a viscosity of 6.05 X
10 7 poises as determined by shearing creep method.
Preparation Example 2 of the adhesive copolymer solution:
760 g of dodecyl methacrylate, 200 g of 2-ethylhexyl
acrylate, 40 g of acrylic acid, 560 g of n-hexane and 120
g of toluene are charged in a 4 Q four-necked flask
provided with a nitrogen inlet, reflux condenser, stirrer
and thermometer. The whole is heated in a water bath
and stirred while nitrogen is introduced therein. When
the inner temperature reaches 70c, a solution of 12 g
of dodecyl peroxide as initiator in 88 g of n-hexane is
slowly added over a period of about one hour. The
stirring is continued for an additional 7 hours. After
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the completion of the polymerization reactlon, 720 g of
n-hexane is added to the mixture to dilute the same,
thereby obtaining 2500 g of an adhesive solution having
a concentration of about 40 %. The adhesive solution
has a viscosity of 530 poises at 30C as determined by
means of a rotational viscometer. After removal of the
solvent, the resulting thin film of the adhesive solution
has a viscosity of 9.50 X 10 6 poises as determined by
the shearing creep method.
Preparation Example 3 for the adhesive copolymer solution:
950 g of dodecyl methacrylate, 50 g of acrylic acid,
560 g of n-hexane and 120 g of toluene are charged in a
4 Q four-necked flask provided with a nitrogen inlet,
reflux condenser, stirrer and thermometer. The whole is
heated in a water bath and stirred while nitrogen is
introduced therein. When the inner temperature reached
70C, a solution of 12 g of dodecyl peroxide as initiator
in 88 g of n-hexane is slowly added over a period of
about one hour. The stirring is continued for an addi-
tional 7 hours. After completion of the polymerization
reaction, 720 g of n-hexane is added to the mixture to
dilute it, thereby obtaining 2500 g of an adhesive solu-
tion having a concentration of about 40 %. The adhesive
solution has a viscosity of 378 poises as determined by
~L~757~
means of a rotational viscometer at 30C. After removal
of the solvent, the resulting thin film of the adhesive
has a viscosity of 3.41 X 10 7 poises as determined by
the shearing creep method.
The following examples will further illustrate, but
by no means llmit, the present invention.
Example 1
160 g (i.e. 40 % based on the solid content of
adhesive solutionj of 5 % solution of nitroglycerin in
ethyl acetate was added to 1000 g of the adhesive
copolymer solution obtained in the above Preparation
Example 1 and the whole was thoroughly stirred to obtain
a mixture. The resulting nitroglycerin-containing
adhesive composition was uniformly applied to the surface
of a silicone-treated polypropylene film separator 80 ~m
thick so that the solid content of the adhesive com-
position would be 40 g/m2. The solvent was volatilized
out to obtain a nitroglycerin-containing adhesive com-
position in the form of a sheet.
Separately, one surface of a flexible polyethylene
film 80 ~m thick was mat-finished and the other surface
was corona-treated to obtain a base.
The adhesive composition layer of the adhesive
composition sheet provided with the separator and the
corona-treated surface of the base were adhered together,
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thereby transferring the adhesive composition from the
separator to the polyethylene film base. Thus, a medi-
cinal adhesive sheet containing 8 mg/lO0 cm2 of nitro-
glycerin was obtained. The sheet was cut into pieces of
a given size and each piece was sealed in an aluminum-
laminated polyethylene bag.
Results of elution test of the medicinal adhesive
sheet wherein a phosphate buffer physiological salt
solution (pH 6.0) was used are summarized in following
Table l.
Example 2
~ n example of the precise transfer method of the
present invention will be illustrated with reference to
Fig. 2, which faciliates understanding this example.
Adhesive solution (2) obtained from the above
Preparation Example 2 was uniformly applied to a release
paper (l) laminated with a silicone-treated polyethylene
layer in such a manner that the solid content would be
32 g/m2, and then it was dried [see Fig. 2-(a)]. Adhesive
(2) on the release paper was affixed to the corona-treated
surface of base (3) comprising a flexible polyethylene
film 8 ~m thick with one mat-finished surface and one
corona-treated surface to obtain a polyethylene sheet in
which the copolymer was interposed between the release
paper and the base [Fig. 2-(b)]o
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Then, ointment t5) comprising refined lanolin with
10 % of uniformly dispersed nitroglycerin was applied in
an amount of 8 g/m2 to the silicone surface of a silicone-
treated polyethylene terephthalate film separator (4)
having a thickness of 80 ~m [Fig. 2-(d)]. The said surface
is attached to the adhesive surface (2) [Fig. 2-(c)]
exposed by removing the release paper from the polyethylene
sheet ~Fig. 2-(e)]. ~fter aglng at 40C for approximately
7 days, a nitroglycerln-containing adhesive sheet (nitro-
glycerin content: 8 mg/100 cm2) having a polyethylene base
and a polyethylene terephthalate separator [Fig. 2-(f)]
was obtained. The sheet was cut into pieces of a given
size and each piece was sealed in an aluminum-laminated
polyethylene bag. The bags were stored. Results of an
elution test of the medicinal adhesive sheet using a
phosphate buffer physiological salt solution (pH 6.0) are
summarized in Table 1. The steps of this example are
shown in Fig. 2.
Example 3
20 g of white petrolatum and 140 g of refined
lanolin was added to 1003 g of the adhesive solution
obtained in Preparation Example 3, and the whole was
thoroughly stirred to obtain a solution. Then 224 g
(i.e. 40 % based on the solid copolymer content) of 5 %
solution of nitroglycerin in ethyl acetate was added to
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the adhesive composition to obtain a mixture. The
nitroglycerin-containing adhesive solution was uniformly
applied to a silicone-treated polypropylene film separator
having a thickness of 80 ~m so that the solid content
would be 40 g/m2. The solvent was volatilized to obtain
an adhesive composition sheet.
Separately, one surface of a flexible polyethylene
film 80 ~m thick was mat-finished and the other surface
was corona-treated to obtain a base.
The adhesive surface of the adhesive composition
sheet was attached to the corona-treated surface of the
base to obtain a medicinal adhesive sheet containing 8
mg/100 cm2 of nitroglycerin. The sheet was cut into
pieces of a given size and each piece was sealed in an
aluminum-laminated polyethylene bag. The bags were stored.
Results of elution test of the medicinal adhesive sheet
using a phosphate buffer physiological salt solution
(pH 6.0) are summarized in Table 1.
Example 4
160 g (i.e. 40 % based on the solid content of the
adhesive solution) of 5 % solution of nitroglycerin in
ethyl acetate was added to 1000 g of the adhesive solu-
tion obtained in Preparation Example 2 and the mixture
was stirred thoroughly. The nitroglycerin-containing
adhesive solution was uniformly applied to a silicone-
1~7~7~
- 22 -
treated polyethylene terephthalate film separator having
a thickness of 80 ~m so that the solid copolymer content
would be 40 g/m2. The solvent was volatilized to obtain
an adhesive composition sheet.
Separately, one surface of a flexible polyethylene
film 80 ~m thick was mat-finished and the other surface
was corona-treated to obtain a base.
The adhesive layer surface of the adhesive composi-
tion sheet was attached to the corona-treated surface of
the base to obtain a nitroglycerin-containing medicinal
adhesive sheet having a nitroglycerin content of 8 mg/
lO0 cm2. The sheet was cut into pieces of a given size
and each piece was sealed in an aluminum-laminated
polyethylene bag. The bags were stored. Results of
elution test of the medicinal adhesive sheet using a
phosphate buffer physiological salt solution (pH 6.0)
are summarized in Table 1 given below.
Referential Example l: Elution test of nitroglycerin-
containing medicinal adhesive sheetO
Nitroglycerin elution test of a nitroglycerin-
containing medicinal adhesive sheet was carried out
using a phosphate buffer physiological salt solution
(0.05 mol, pH 6.0). The nitroglycerin-containing adhesive
sheet was cut into round pieces having a radius of 2 cm
~75~9~6
- 23 ~
and applied to a cellulose film, then mounted on a fixing
table on an acrylic disc. It was immersed in 50 mQ of
the phosphate buffer physiological salt solution at 37C
and the solution was slowly stirred at a given rate.
Amounts of nitroglycerin eluted out through the cellulose
film after one, two and four hours were measured by means
of a microbonder pack C1 8 (a product of Waters) column by
high performance liquid chromatography.
The results of the analysis of the samples in
Examples 1 to 4 are summari~ed in Table 1. All of the
samples of the present invention exhibited a higher
nitroglycerin elution than that of a sample prepared by
using a commercially available acrylic adhesive.
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Table 1
Results of elution tests of ni.troglycerin-
containing adhesive sheets
. .
Sample Elution time (hr.)
.
1 2 4
Medicinal adhesive sheet 46.5 60.1 78.8
of Example 1
Medicinal adhesive sheet 55.7 72.6 89.7
of Example 2
Medicinal adhesive sheet 49.2 62.4 80.2
of Example 3
Medicinal adhesive sheet 53.4 74.7 92.4
of Example 4
Tape containing commercially 18.0 26.7 35.0
available acrylic adhesive *
Numerals in Table 1 are elution rates (~) into
the phosphate buffer physiological salt solution (pH 6.0).
The initial nitroglycerin con-tent of the sheet is shown
as 100 ~.
* Tape pieces were prepared in the same manner as in
Example 1 except that a commercially available
acrylic adhesive (the same copolymer as in above
sample A was used.
Reference Example 2: Nitroglycerin residue in the nitro-
glycerin-containing adhesive sheet after the application
thereof.
A nitroglycerin-containing adhesive tape was applied
~757~6
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to the inner side of the forearm of each of three normal
male human subjects. After a given period of time, the
adhesive tape was peeled off and the amount of nitro-
glycerin remaining in the tape was measured by HPLC. The
results are summarized in Table 2.
Table 2
Sample Application time (hr.)
1 2 4 8
Medicinal adhesive tape 96.2 94.3 82.9 64.8
of Example 1
Medicinal adhesive tape 91.6 84.2 78.4 62.7
of Example 2
Medicinal adhesive tape 98.5 92.6 80.4 65.2
of Example 3
Medicinal adhesive tape 84.9 81.3 73.7 59.0
of Example 4
Tape containing commer-
cially available 100.1 94.1 90.7 79.4
acylic adhesive *
* Same sample as in Table 1.
Numerals in Table 2 are nitroglycerin residues (g6)
in the nitroglycerin-containing adhesive tapes after
they were applied to an inner side of the forearms of
three normal male human subjectsD The initial value is
represented as 100 g6.
In all of the medicinal adhesive tapes according
to the present invention containing dodecyl methacrylate
as the main ingredient, the nitroglycerin residue after
~7s7a~6
- 26 -
application was smaller than that of tne commercially
available acrylic adheslve-containing tape. The balance
obtained by deducting the residue (%) from the initial
value (100 %) indicates the percutaneous absorption.
Accordingly, the nitroglycerin-containing adhesive sheet
of the present invention shows high percutaneous absorp-
tion.
Reference Example 3: Changes in blood pressure and heart
rate due to the nitroglycerin-containing adhesive sheet.
The nitroglycerin-containing adhesive sheet of
Example 4 was applied to a normal male human subject
(age: 38) and his blood pressure, heart rate and electro-
cardiogram (lead II~ were recorded. He was kept resting
lying on his back from 30 minutes before the application.
The said sheet (5 X 10 cm2) (actual nitroglycerin content:
4.1 mg) was applied to the inner side of one forearm of
the subject. slood pressure and electrocardiogram were
measured at 10 minute intervals and the heart rate was
measured continuously. The test was continued for two
hours. The results are summarized in Fig. 1.
The blood pressure reduction or heart rate increase
and palpitation began about 20 minutes after the applica-
tion of the sample sheet. The subject complained of a
weak headache 60 minutes after application. The palpitation
~7S7~3Ei
- 27 -
of the subject became severe 90 minutes after application.
The blood pressure reduction and heart rate increase
substantially coincided with the appearance of the sub-
jective symptoms of the patient, but influences on the
electrocardiogram were hardly observed. It is apparent,
therefore, that the medicinal adhesive sheet of the
present invention is suitable for the treatment of heart
diseases and prevention of an attack if the area of the
sheet tamount of the medicinej is suitably determined.
Industrial Utility
The medicinal adhesive sheet of the present invention
has an excellent nitroglycerin-releasing property and can
be easily used. The sheet, therefore, can be used for the
treatment and prevention of ischemic heart diseases such
as angina pectoris. It is expected, therefore, that the
present invention will contribute to the development of
the pharmaceutical industry.
